The advantages of the transdermal administration of drugs over other routes are well known. Nevertheless, the skin permeation of the majority of the drugs is not enough to provide suitable therapeutic levels. The skin, particularly the stratum corneum, provides a barrier for the permeation of many substances. Several alternatives have been proposed to solve this problem, most of them based on the use of a suitable permeation enhancer.
In comparison with the conventional administration routes of potent drugs, the transdermal administration offers important advantages. The main reasons are its simplicity and that the administration is not invasive. Moreover, those devices have more bioavailability than the oral route because the drug avoids the first pass through the digestive system where it is sometimes metabolised or inactivated in significant proportions. Besides, its administration can be immediately interrupted if side effects are detected.
Generally, the transdermal route of administration offers the potential benefits of simplicity, efficacy and acceptability by the patient. This acceptance is essential for any treatment with this type of devices and so they must be substantially comfortable: they should not be bulky, they should be aesthetically pleasant to sight and touch, should be maintained correctly affixed to the patient's skin during the period of use and should be easily detached when required.
Theoretically, transdermal administration devices should provide a steady plasmatic concentration during an extensive period of time, with an acceptable variability between patents. The physicochemical and physiological principles that governs the absorption of drugs through the transdermal route are well known.
In the literature several devices have been described for the transdermal administration of drugs.
The skin is, generally, an effective barrier for the permeation of drugs and the diffusion of them is slower than through other membranes of the organism. The simple occlusion of the skin by means of non-permeable barriers increases the hydration of the stratum corneum, increasing markedly the permeation of drugs compared to the skin without occlusion.
Further the vehicle in which the drug is dissolved can also contribute to determine the extent of absorption. The addition permeation enhancers can increase several fold the absorption of some drugs. The term “penetration” is used for the income of the drug to the skin and “permeation” for the process of crossing the skin and arrival to the circulation, even though there is not an absolute demarcation between both processes.
The transdermal delivery devices should be formulated so that the contained drugs have a penetration and a permeation according to the propose of the product.
Nowadays there are different types of transdermal devices. Nevertheless, these devices could be grouped in two main categories: reservoir-type devices and matrix-type devices. In the literature other types of device have been described, but all of them could be considered as extensions of one of these groups or as combinations of them.
The transdermal devices of reservoir-type contain a reservoir that contains the active pharmaceutical ingredient (API). From that reservoir, the API diffuses through the controlling membrane to the site of absorption. The controlling membrane could be microporous or continuous. These devices usually have a backing layer, a reservoir that contains the drug, a controlling membrane, an adhesive layer and a release or protective layer. The main advantage of this type of device is that the rate of drug delivery is maintained practically constant for long periods of time. Nevertheless, these devices are usually bulky (voluminous), they have a total surface that is bigger than the active surface and, besides, they have the disadvantage that the rupture of the controlling membrane could produce a higher release than desired.
There are several transdermal devices of this type in the market, which differ from each other in the reservoir of the drug. The reservoir can be a polymer, a liquid, a gel or a cream, in which the drug is dissolved or dispersed.
Within the group of patches with reservoir, the transdermal devices with multireservoirs with controlling membrane as well as the devices with reservoir and without controlling membrane can be included. The main characteristic of the first type is that the permeation enhancer agent is stored in a compartment separated from the drug reservoir and that of the second type is that an adhesive layer not loaded with drug functions as the control of the permeation.
On the other hand, matrix-type transdermal devices comprise, generally, a nonpermeable backing liner, a polymeric adhesive matrix in which the active drug or drugs are dissolved or dispersed and a release liner. They have a total surface area that is the same as that of the active surface. Generally, this type of device has had greater acceptance by patients than the reservoir-type patches.
The current trend in the design of transdermal delivery devices is directed to matrix-type devices. This is not only because the production costs are lower, but because it is possible to obtain devices with greater versatility than the reservoir-type ones.
One disadvantage of the matrix-type devices is that, for some active substances, it is difficult to maintain a constant dose for extended periods of time. Generally, in this type of device, the delivery rate diminishes with the time as a consequence of the decrease of the concentration of the API in the matrix.
The addition of polymeric layers acting as controlling membranes for the drugs has not been completely successful because they are usually less comfortable to use by the patient, mainly because their mechanical properties became worse with the mentioned addition. Another problem to be solved in this type of device is the one related to physical stability because, generally, to assure a constant delivery, the active substance needs to be present in a saturation or supersaturated concentration. Besides, it is important for the comfort of the user that the size of the device should be as small as possible.
Finally, it is very important that the transdermal device has enough adhesiveness to be able to remain on the application site assuring suitable drug delivery during the necessary period of time, while having, at the same time, a painless removal, which is not easy to obtain.
In literature several documents that disclose devices for transdermal administration comprising two or more adhesive layers can be found.
As examples, U.S. Pat. No. 4,031,894, U.S. Pat. No. 4,060,084, U.S. Pat. No. 4,262,003, U.S. Pat. No. 4,436,741 and U.S. Pat. No. 4,201,211 (Alza Corporation) disclose devices with reservoir and rate controlling membrane for the transdermal administration of drugs that deliver an initial pulse followed by a substantially constant dosage. According to those documents, the preferred embodiment consists in a therapeutic system in the form of a bandage with four layers that comprise: a) a protective backing layer, b) a reservoir layer that comprises the a pharmaceutical active drug (for example scopolamine, clonidine, etc.) dispersed in a mixture of a mineral oil gel and polyisobutylene, c) a microporous membrane that control the rate at which the drug is released and d) an adhesive layer.
U.S. Pat. No. 5,310,559 (Hercon Laboratories Corporation) disclose devices with reservoir and controlling rate membrane with a structure similar to the ones already mentioned that include the use of the copolymers of acrylate-olefin as control rate membrane of the active substances.
U.S. Pat. No. 5,004,610 (Alza Corporation) discloses a device with reservoir and controlling rate membrane, for the administration of nicotine. According to the disclosure, nicotine is dissolved within said reservoir in a solvent (preferably a copolymer of ethylene-vinyl acetate) with a concentration below its saturation.
All the devices in the documents above mentioned belong to the type “with reservoir and controlling rate membrane” and present the disadvantages and objections previously mentioned. It is important to note that for the controlled drug flux, these devices need the addition of a controlling membrane and cannot perform adequately without it. The membrane is located between the drug and the adhesive layer and it is a fundamental element of the device.
The use of adhesive polymers acting as controlling rate membranes or a control of the final flux of the drug to the skin has been described.
On the other hand, U.S. Pat. No. 4,769,028 (Lohmann GmbH & Co.) disclose a device that comprises a reservoir containing several layers, in which the concentration of the drug is supersaturated and increases layer to layer, as the distance to the adhesive layer increases. According to the disclosure, the layers of said reservoir can have the same polymeric composition.
U.S. Pat. No. 4,938,759 (Alza Corporation) discloses a device for the transdermal administration of drugs moderately soluble in mineral oil and that have a melting point higher than 50° C., comprising a reservoir layer that consists of a dispersion of the drug in a ethylene-vinyl acetate copolymer in a concentration higher than saturation. In the same way, U.S. Pat. No. 6,174,545 (Alza Corporation) and U.S. Pat. No. 6,074,665 (LTS Lohmann Therapie-Systeme GMBH) require that the drug should be dispersed under supersaturated concentrations.
The main disadvantage of this type of device is the use of high amounts of drug to supersaturate all the layers. As a consequence, the supersaturation can make the device unstable, producing the crystallisation of the drug and making the device physically unstable. Moreover, the necessity of using many layers, as for example the ones required for the device disclosed in U.S. Pat. No. 4,769,028, produce an increase of the final thickness of the device that impairs its mechanical properties. Finally, this type of device needs also a complex and extensive manufacture process that can raise the production costs and consequently the price of the final product.
On the other hand, U.S. Pat. No. 4,906,463 and U.S. Pat. No. 5,006,342 disclose the use of a multiplicity of spaced structural layers, to provide better mechanical properties in a device for transdermal administration. The main disadvantage of this type of device is that it often presents a high inter-patient variability for the delivery of the drug, which makes it unsuitable for treatments with drugs whose application window should be strictly fixed (see for example Anesthesiology, 83, 459-469 (1995)).
WO 0126705 (Samyang Corporation) disclose a device for the transdermal administration of drugs that comprises two layers of adhesive, wherein each layer is positioned adjacent to the other, containing each one the same drug and being both laminated over the same backing layer.
Additionally, WO 0139754 (Pierre Fabre Medicament) disclose adhesive patches comprising two chambers such that the first chamber is a reservoir-type transdermal device and the second chamber is matrix-type transdermal device located at the periphery of the first chamber. Said two chambers contain the same active substance.
Both aforementioned WO applications describe products that are difficult to manufacture. Besides, as each layer functions independently, both of them should be in contact with the skin, increasing the surface of the device.
Additionally, it has been described that, in order to achieve optimal adhesive or retention properties, it possible to combine commercial adhesives to obtain better formulations. In those prior art documents, it has been stated that using certain mixtures it is possible to modulate the amount of drug to be used or to increase or diminish the drug flux of the active drug (see for example U.S. Pat. No. 5,474,783, U.S. Pat. No. 5,656,286, U.S. Pat. No. 5,958,446, U.S. Pat. No. 6,024,976, U.S. Pat. No. 6,221,383, U.S. Pat. No. 6,235,306, WO 0041538).
WO 02/26217 describes, but does not exemplify, a transdermal drug delivery device having two layers of different composition and a backing layer, called an adhesive rate controlled system. The layer adhered to the backing is a drug reservoir and the other layer is a rate controlling layer which in use contacts the skin. The two layers have different affinity for the drug, the skin-contacting layer having a lower affinity. The difference of affinity allows the delivery rate to be controlled.